V Rickert1, L Wagenhäuser1, P Nordbeck2,3, C Wanner2,4, C Sommer1,2, S Rost5, N Üçeyler1,2. 1. From the, Department of Neurology, University of Würzburg, Würzburg, Germany. 2. Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), University of Würzburg, Würzburg, Germany. 3. Department of Internal Medicine, Division of Cardiology, University of Würzburg, Würzburg, Germany. 4. Department of Internal Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany. 5. Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
Abstract
BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the α-galactosidase A (α-GalA) gene. We investigated the impact of individual amino acid exchanges in the α-GalA 3D-structure on the clinical phenotype of FD patients. PATIENTS AND METHODS: We enrolled 80 adult FD patients with α-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α-GalA 3D-structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. RESULTS: Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). CONCLUSIONS: The type of amino acid exchange location in the α-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.
BACKGROUND:Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the α-galactosidase A (α-GalA) gene. We investigated the impact of individual amino acid exchanges in the α-GalA 3D-structure on the clinical phenotype of FDpatients. PATIENTS AND METHODS: We enrolled 80 adult FDpatients with α-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α-GalA 3D-structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. RESULTS:Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). CONCLUSIONS: The type of amino acid exchange location in the α-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FDpatients.